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Constitutive RAC activation is not sufficient to initiate melanocyte neoplasia but accelerates malignant progression


Dalton, Lucy E; Kamarashev, Jivko; Barinaga-Rementeria Ramirez, Irene; White, Gavin; Malliri, Angeliki; Hurlstone, Adam (2013). Constitutive RAC activation is not sufficient to initiate melanocyte neoplasia but accelerates malignant progression. Journal of Investigative Dermatology, 133(6):1572-1581.

Abstract

Deregulated Ras signaling initiates and maintains melanocyte neoplasia. The Rho-like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras/Raf/mitogen-activated protein kinase signaling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Furthermore, we did not detect an additive effect when combined with V600EBRAF, nor could V12RAC1 substitute for suppressed Pi3k signaling to restore melanoma progression. However, coexpression of V12RAC1 and oncogenic RAS accelerated tumor nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 (T-cell lymphoma invasion and metastasis 1) is overexpressed in melanoma tumor nodules in both zebrafish and humans. Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations.

Abstract

Deregulated Ras signaling initiates and maintains melanocyte neoplasia. The Rho-like GTPase Rac has been implicated in Ras-induced neoplastic transformation. Moreover, a recurrent UV-induced mutation activating RAC1 has recently been detected in human melanoma. Here, a role for Rac in melanoma initiation and progression was investigated in human melanomas and zebrafish models of melanocyte neoplasia. Immunohistochemical analysis revealed RAC expression and activity restricted to melanocytes at the junction of the epidermis and dermis in benign neoplasms. Malignant melanocytes displayed elevated RAC activity that extended into the suprabasal epidermis, deeper into the dermis, and was maintained in metastases. Previously, we have used zebrafish transgenic models to demonstrate that deregulated Ras/Raf/mitogen-activated protein kinase signaling can initiate melanocyte neoplasia. Expression of a constitutively active RAC1 mutant (V12RAC1) was not sufficient to initiate melanocyte neoplasia in this organism. Furthermore, we did not detect an additive effect when combined with V600EBRAF, nor could V12RAC1 substitute for suppressed Pi3k signaling to restore melanoma progression. However, coexpression of V12RAC1 and oncogenic RAS accelerated tumor nodule formation. Immunohistochemical analysis revealed that the Rac activator Tiam1 (T-cell lymphoma invasion and metastasis 1) is overexpressed in melanoma tumor nodules in both zebrafish and humans. Thus, our data suggest that Rac contributes to the progression of melanoma and that Tiam1 may activate Rac in nodular presentations.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2013
Deposited On:11 Feb 2014 15:29
Last Modified:05 Apr 2016 17:35
Publisher:Nature Publishing Group
ISSN:0022-202X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/jid.2013.23
PubMed ID:23337888

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